US5091429A - Derivatives of 4-amino-1-trifluoromethyltetralines their preparation and their therapeutic application - Google Patents

Derivatives of 4-amino-1-trifluoromethyltetralines their preparation and their therapeutic application Download PDF

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US5091429A
US5091429A US07/391,582 US39158289A US5091429A US 5091429 A US5091429 A US 5091429A US 39158289 A US39158289 A US 39158289A US 5091429 A US5091429 A US 5091429A
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group
formula
pharmaceutical composition
hydrogen atom
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Jean-Pierre Begue
Micheline Charpentiermorize
Daniele Bonnet Delpon
Huguette Gilbert-Semon
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Laboratoires Lucien
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to derivatives of 4-amino-1-trifluoromethyltetraline, the process for their preparation and their therapeutic application.
  • the applicant has now found aminotetralines, and acid addition salts thereof, having a trifluoromethyl group on an alicyclic carbon in place of a hydrogen atom and having antidepressant and analgesic activities.
  • the applicant has developed new processes for the preparation of trifluoromethylated tetralines useful, in particular, in the synthesis of trifluoromethylated aminotetralines.
  • the object of the present invention is the derivatives of 4-amino-1-trifluoromethyltetralines of general formula: ##STR2## wherein: X represents an aromatic nucleus, namely phenyl, naphthyl ⁇ or ⁇ thienyl able to carry one to two substituents chosen from halogeno, hydroxy, C 1 to C 8 alkoxy, trifluoromethyl;
  • R 1 represents a hydrogen atom or a halogen, a hydroxy group, a C 1 to C 8 alkoxy group, in one of positions 5, 6 or 7, or even a methylenedioxy group in positions 5 and 6 or 6 and 7;
  • R 2 represents a hydrogen or halogen atom, a hydroxy group, a C 1 to C 8 alkoxy group in one of the other positions 5, 6 or 7, and
  • R 3 and R 4 each represents a hydrogen atom, a linear or branched C 1 to C n alkyl group, n being 2 or more, possibly halogenated, hydroxylated or aminated, or R 3 and R 4 together with the nitrogen atom to which they are linked form a saturated heterocyclic compound, possibly substituted, with five or six atoms of which one or two are heteroatoms chosen from nitrogen, oxygen or sulfur.
  • a preferred class of compounds comprises the derivatives wherein X is a phenyl ring able to carry one to two substituents chosen from halogeno, hydroxy, C 1 to C 8 alkoxy or trifluoromethyl.
  • the compounds of formula I have an amine function on carbon number 4; depending on the nature of R 3 and R 4 , the compounds of the invention can thus be primary amines, secondary amines or tertiary amines; the following can be given as examples:
  • R 3 represents a hydrogen atom and R 4 represents a methyl group or a group of formula --(CH 2 ) n --OH in which n is 2 or more;
  • halogens chlorine and fluorine are particularly preferred.
  • salts comprise acid addition salts which are formed with various mineral and organic acids, for example, halohydrates, sulfates, nitrates, tartrates, mandelates, acetates, succinates, benzenesulfonates.
  • the compounds of the present invention can be prepared using the various processes described hereinafter.
  • the compounds of formula I can be prepared from derivatives of 1-aryl-1-trifluoromethyltetralines having the following formula: ##STR4## wherein R 1 , R 2 and X have the same meaning as in formula I.
  • the derivatives of 1-aryl-1-trifluoromethyltetralines (II) can, if the case arises, be prepared by solvolysis of the corresponding derivatives (known) of 5-aryl-1,1,1-trifluoro-pentan-2-ol of formula: ##STR5## wherein R 1 , R 2 and X have the same meaning as in formula I.
  • a first process for the preparation of a compound of formula I consists in halogenating a derivative of 1-aryl-1-trifluoromethyltetraline of formula II wherein R 1 , R 2 and X have the same meaning as in formula I to obtain the corresponding halide of formula: ##STR6##
  • R 1 , R 2 and X have the same meaning as in formula I and A represents a halogen, to be reacted over the latter an amine of formula: ##STR32## wherein R 3 and R 4 have the same meaning as in formula I to obtain a mixture of the two diastereoisomers of the corresponding compound of formula I.
  • halogenation reaction of a derivative of 1-aryl-1-trifluoromethyl tetraline (II), according to the present process is advantageously carried out with a halogenosuccinimide under reflux with CCl 4 and in the presence of benzoyl peroxide.
  • reaction between the halide of formula III and the amine of formula IV according to the present process is preferentially carried out in toluenic solution for over 24 hours and at room temperature.
  • the compounds of formula I wherein R 3 or R 4 , or R 3 and R 4 represent a hydrogen atom can also be prepared by a second process which consists in oxidizing a derivative of formula II to obtain the corresponding tetralone of formula ##STR33## wherein R 1 , R 2 and X have the same meaning as in formula I, by reacting the latter with an amine of formula IV wherein R 3 or R 4 , or R 3 and R 4 represent a hydrogen atom, to obtain a nitrogenated residue which is reduced by a hydride to obtain the corresponding compound of formula I, which is a primary amine (R 3 or R 4 represent a hydrogen atom) or a secondary amine (R 3 or R 4 represent a hydrogen atom).
  • FIG. 1 represents the general reactional diagram according to the first process for the preparation of compounds of formula I.
  • FIG. 2 represents the general reactional diagram according to the second process for the preparation of compounds of formula I wherein R 3 or R 4 , or R 3 and R 4 represent a hydrogen atom.
  • R 1 and R 2 each represent a hydrogen atom
  • X represents a phenyl ring
  • R 3 and R 4 together with the nitrogen atom to which they are linked form a group of formula ##STR34## in formula I).
  • R 1 and R 3 each represent a hydrogen atom, X represents a phenyl group, R 1 represents a methoxy group in position 7 and R 4 represents a methyl group, in formula I).
  • Determination of mortality in the mouse is observed following unique administration by oral route of increasing doses of the compounds to be tested.
  • the LD 100 for all the compounds studied is greater or equal to 400 mg/kg, for example, that of compound 4a is greater than or equal to 800 mg/kg.
  • the LD 0 and LD 100 of compounds N o . 1, 2, 3, 4a, 4b and 5b are grouped together in the following table:
  • This consists of measuring the time for appearance of a nociceptive reaction to a thermoalgesic stimulus in the mouse.
  • the animal is placed on a metal plate maintained at a constant temperature of 56° C. It reacts by licking its back paws in a time ranging from 4 to 12 seconds. After administration of an analgesic, the time taken for the reflex to appear is longer: an increase in threshold is obtained.
  • the maximal exposure time is limited to 30 seconds, taken as an arbitrary lapse of time indicating total analgesia.
  • This study used for the selection of analgesics, consists of investigating the possible protection against abdominal spasms and/or contortions provoked, in the mouse, by intraperitoneal injection of acetic acid.
  • a depressive state can be induced in the mouse by forcing it to swim in a narrow, cylindrical container from which it cannot escape. After a brief period of intense activity, the mouse adopts a characteristic immobile position that is easily identifiable.
  • Antidepressants reduce this immobility.
  • This exploration test in the mouse consists of measuring, in a special enclosure, the time after which the first exploration begins and the total number of explorations throughout the duration of the test. Oral administration of a dose ranging from 20 mg/kg to 100 mg/kg of compounds N o . 1, 2, 3, 4a, 4b and 5b in hydrochlorate form does not lead to any modification in the behaviour of animals.
  • This test consists of investigating an effect on the central nervous system by studying exploration and response to different reflexes in the mouse: corneal, auricular, straightening up, tensing up and clinging.
  • Oral administration of a dose ranging from 20 mg/kg to 100 mg/kg of compounds N o . 1, 2, 3, 4a, 4b and 5b in hydrochlorate form does not have any effect on the central nervous system of animals.
  • the invention thus also relates to pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable agent or excipient.
  • the drugs can be presented, for example, in the form of tablets, vials for injection, suppositories or capsules at doses ranging from 10 mg to 500 mg per dose.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
US07/391,582 1987-11-26 1988-11-24 Derivatives of 4-amino-1-trifluoromethyltetralines their preparation and their therapeutic application Expired - Fee Related US5091429A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8716436A FR2623802B1 (fr) 1987-11-26 1987-11-26 Derives d'amino-4 trifluoromethyl-1 tetralines. leur preparation et leur application en therapeutique
FR8716436 1987-11-26

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US (1) US5091429A (de)
EP (1) EP0346419B1 (de)
JP (1) JPH02502380A (de)
AT (1) ATE76398T1 (de)
DE (1) DE3871383D1 (de)
FR (1) FR2623802B1 (de)
WO (1) WO1989004820A1 (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5545755A (en) * 1989-05-31 1996-08-13 The Upjohn Company Therapeutically useful 2-aminotetralin derivatives
US20070197588A1 (en) * 2006-01-06 2007-08-23 Sepracor Inc. Tetralone-based monoamine reuptake inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2665443B1 (fr) * 1990-08-03 1992-11-06 Lucien Laboratoires Derives d'amino-4-methyl-1-tetralines, leur preparation et leur application en therapeutique.

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1420472A (en) * 1972-09-27 1976-01-07 Pfizer Aminophenyltetralin compounds
US4536518A (en) * 1979-11-01 1985-08-20 Pfizer Inc. Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine
US4556676A (en) * 1979-11-01 1985-12-03 Pfizer Inc. Antidepressant derivatives of trans-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1420472A (en) * 1972-09-27 1976-01-07 Pfizer Aminophenyltetralin compounds
US4536518A (en) * 1979-11-01 1985-08-20 Pfizer Inc. Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine
US4556676A (en) * 1979-11-01 1985-12-03 Pfizer Inc. Antidepressant derivatives of trans-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5545755A (en) * 1989-05-31 1996-08-13 The Upjohn Company Therapeutically useful 2-aminotetralin derivatives
US20070197588A1 (en) * 2006-01-06 2007-08-23 Sepracor Inc. Tetralone-based monoamine reuptake inhibitors
US8053603B2 (en) 2006-01-06 2011-11-08 Sunovion Pharmaceuticals Inc. Tetralone-based monoamine reuptake inhibitors
AU2006335174B2 (en) * 2006-01-06 2012-09-06 Sunovion Pharmaceuticals Inc. Tetralone-based monoamine reuptake inhibitors

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EP0346419B1 (de) 1992-05-20
FR2623802A1 (fr) 1989-06-02
FR2623802B1 (fr) 1990-05-04
WO1989004820A1 (fr) 1989-06-01
EP0346419A1 (de) 1989-12-20
JPH02502380A (ja) 1990-08-02
DE3871383D1 (de) 1992-06-25
ATE76398T1 (de) 1992-06-15

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